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The Physiology of Muscles
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The Physiology of Muscles
Part
April, 2023
BY Dr. Dereje Wakgari
Objectives:
 Know the major classes of muscles of the body.
 Describe the molecular basis of muscle contraction.
 Differentiate the roles of Ca2+ in skeletal, cardiac + smooth muscles.
The Physiology of Muscles
Introduction
Part III
1. Introduction
1.1. General Points
a. Can be excited chemically, electrically + mechanically.
b. Contractile mechanisms (actin + myosin) that can be activated by AP.
1.2. Mass
a. 45-50% of the total body mass ( 600 muscles)
b. 40% skeletal muscles + 10% cardiac and smooth muscles (45-50%).
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Introduction
Part III
1.3. O2 consumption
a. 25% total bodily O2 consumption at rest is consumed by the
muscles.
b. During strenuous exercise this amount can increase as much as
10-20 times.
2. Types/Classification
2.1. Anatomical
2.1.1. Striations:
Presence of alternating light and dark bands on the sarcolemma.
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Introduction
Part III
Classification
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Introduction
Part III
2.1.1.1. Skeletal muscle
i. Have well developed cross striations (interdigitating thick and thin filaments).
ii. Voluntary muscle tissue.
iii. Cells are long and multinucleated.
iv. Contract only in response to stimuli (no syncytial bridges between cells).
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Introduction
Part III
2.1.1.2. Cardiac muscle
i. Have cross striation (banding pattern of thick and thin filaments).
ii. Involuntary muscle tissue.
iii. Cells are branched and mononucleated.
iv. Have intercalated disc with gap junctions.
2.1.2. Non-striations/Smooth Muscle
Alternating dark and light bands are absent.
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The Physiology of Muscles
Introduction
Part III
2.1.2.1. Single unit smooth muscle (Visceral smooth muscle)
i. Are large sheets of mononucleated small cells.
ii. Have low resistance bridge of gap junctions.
iii. Show synchronous excitation and contractions.
(= functional syncytium)
iv. Have unstable resting membrane potential.
v. Found in gut, ureter, small blood vessels and uterus.
2.1.2.2. Multiunit smooth muscles
i. Found in iris, lungs, hair roots and large arteries.
ii. Have no gap junctions but each cell receive ANS nerve terminal.
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Introduction
Part III
2.2. Physiological
2.2.1. Voluntary Muscle
• Skeletal muscle (CNS, somatic neurons).
2.2.2. Involuntary muscle
• Cardiac muscle (Intrinsic + Extrinsic factors, ANS + Hormonal)
• Smooth muscle (Intrinsic + Extrinsic factors, ANS + Hormonal)
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The Physiology of Muscles
Skeletal Muscle
Part III
3.0. Skeletal Muscle
• Interactions between the body and the external environment
(maintenance of posture and movement, speech, respiration…).
3.1. Physiological classifications
3.1.1. Type I: Slow twitch oxidative fibers (red muscle)
i. Have slow myosin ATPase activity.
ii. High myoglobin content
iii. Many mitochondria and capillary
iv. Resistant to fatigue, high oxidative capacity
v. Muscles of the back and neck (strong gross sustained movt.)
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The Physiology of Muscles
Skeletal Muscle
Part III
3.1.2. Type IIA: Fast oxidative-glycolytic fibers (red fibers)
i. Fast myosin ATPase activity
ii. Fatigable fibers
iii. Use glycolytic and oxidative ATP sources
3.1.3. Type IIB: Fast glycolytic fibers (white muscles)
i. Fast velocity of contraction
ii. Fast myosin ATPase activity
iii. Glycolysis is the main ATP source
iv. Few myoglobin, mitochondria and blood vessels are present.
v. Muscles of the hand extraocular muscles (fine, rapid, precise movt.)
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Structural arrangement and contractile unit
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Structural arrangement and contractile unit
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Structural arrangement and contractile unit
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Structural arrangement and contractile unit
The Physiology of Muscles
Skeletal Muscles
Part III
3.2. Structural arrangement and contractile unit
Muscle
↓ epimysium
Fasciculus (20 muscle fibers)
↓ perimysium
Muscle fiber (ɵ=10-100 µm, L=30cm, multinucleated)
↓ endomysium (Sarcolemma, sarcoplasm/myoplasm
Sarcoplasm reticulum
Myofibril (ɵ= 1-2µm, longitudinal, Sarcomere,
75% muscle vol., Z-line, α-actinin, desmin)
Myofilaments
Thick filaments
1500 molecules, myosin
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The Physiology of Muscles
Thin filaments
3000 molecules, actin
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The Physiology of Muscles
Skeletal Muscles
Part III
Terms
1. Epimysium: a connective tissue which ensheaths the entire muscle.
2. Perimysium: a connective tissue that ensheaths the fascicles
3. Endomysium: a sheath that covers each muscle fiber.
• Each one is the continuation of the other.
4. Sarcoplasmic Reticulum: a tubular network that divides the individual
skeletal muscle fiber into myofibrils.
5. Sarcolemma: a true plasma membrane of skeletal muscle fiber.
6. α-actinin: a protein that connects actin to the z-line.
7. Myoplasm/sarcoplsam: cytoplasm of the muscle cell.
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8. Desmin: a protein that links adjacent myofibrils, binding z lines to plm
9. Myosin: the thick contractile protein.
10. Actin: the thin contractile protein.
11. Dystropin: actin binding protein linking transmembrane protein, βdystroglycan, in the sarcolemma with cytoplasmic protein
syntrophins (α-dystroglycan, (sarcoglycan, α, β, γ, δ))
12. Titin: tethers myosin to z lines, serves as a scaffold for sarcomere.
(prevents overstretching of sarcomere, ?cell signaling? Stretch sensor, Titinopathies)
13. Nebulin: a template protein which determines the precise size of actin
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Geometrical orientation of the contractile elements
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Geometrical orientation of the contractile elements
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Skeletal Muscles
Part III
3.3. Functional unit (Sarcomere)
a. It is the distance between two z-lines.
b. Responsible for the striated appearance.
3.3.1. Dimensions
a. The resting length of a sarcomere is 2µm-2.2µm.
b. At this length it generates the greatest force of contraction.
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3.3.2. Molecular geometry
• Differences in Refractive indices When viewed under polarized
light.
A-Band (A= Anisotropisch)*
a. The darker area in the centre of the sarcomere.
b. It is due to the orderly arrangement of thick filaments.
c. Thin filaments may extend into the A-band.
H-Band (H = Hensen’s disc, ?Hell?)
a. It contains only myosin tails (no myosin heads/no cross-bridges)
b. There are no thin filaments.
c. When the muscle is relaxed
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* Germanic words
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M-line (M= Mittelmembran)
a. Site of the reversal polarity of the myosin molecules in each of
the thick filaments.
b. It vertically bisects the H-Band
c. It contains 2 important proteins:
• Myomesin: a structural protein that links neighboring thick filaments
• Creatinine Phosphokinase: an enzyme that maintains adequate
ATP conc. in working muscle fibers.
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I-Band (I= Isotropisch)
a. The lighter area on either side of the z-lines.
b.
Each sarcomere contain half of the two I-bands.
Z-Line/Disc (Z = Zwischenscheibe)
a. Dense line in the center of each light band.
b. Separates one sarcomere from the next.
c. It is the attachment site for the thin filaments.
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NB
1. During muscular contraction:
a. There is NO CHANGE in length of either the thick or the thin
filaments.
b. H-zone disappears and Z-line gets considerably darker.
c. There is shortening of the sarcomere
(↓ I-band and H zone, and A-band remains κ)
2. a. When a muscle increases its length → ↑ in the No of sarcomeres
(NOT the length of each sarcomere)
b. The length of thick & thin filaments of sarcomeres is identical
in a neonate & in the adult muscle.
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3.4. Molecular Basis of Contraction
3.4.1. Sliding-Filament Model (Hanson & Huxley, 1955)
This model theorizes that sliding in of the filaments (thick &
thin) toward the center of muscle and sarcomere is responsible
for the shortening and force of contraction.
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3.4.2 Thick Filament
a. It is called myosin (an actin-binding protein).
b. Dimensions: ɵ = 11-18 nm, L = 1.6 µm
c. Composition of Myosin:
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3.4.3. Thin Filaments
a. They are called actin
c. Components :
1. Globular proteins
i. Actin
ii. Troponin (50 molecules)
2. Non-Globular proteins: tropomyosin (40-60 molecules, 70kD)
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3.4.4 Regulatory proteins
A. Tropomyosin
a. It blocks the binding sites of myosin on actin.
B. Troponins
~ Small globular units located at intervals along the tropomyosin molecules.
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Actins, Troponins and Tropomyosin Filaments
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b. Contractile state:
• The invading action potential to T-Tubule → Ca2+ released from
SR → binds to troponin C → binding of troponin I to actin is
weakened → tropomyosin moves laterally → uncovers binding
sites for myosin heads → contraction (in the presence of ATP).
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3.5.2. Regulatory action of calcium
2 tubular networks (Sarcotubular system) that are involved with
Ca2+:
 Transverse Tubule (T-tube)
 Sarcoplasm Reticulum (SR)
. Functions:
i. Stores Ca2+ in the terminal cisternae
(lateral sacs, 1calsequestrin = 43 Ca2+ )
ii. Uptake and release of Ca2+
NB Calsequestrin is sarcoplasmic protein that binds Calcium.
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3.5.3. Regulation of ATP
a. Actin + myosin + ATP + Ca2+ → CONTRACTION
b. Actin + myosin + ATP - Ca2+ → RELAXATION
c. ATP is needed for relaxation
e. 3 ATP molecules are needed:
i. For the formation of the actinmyosin complex
ii. For the initiation of relaxation.
iii. To pump out Ca2+ from the sarcoplasm to sequester it
into the SR (Ca2+ - Mg2+ pump)
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The Physiology of Muscles
Skeletal Muscles: ECC
Part III
3.6.1. Excitation-Contraction Coupling/
Electromechanical Coupling
Def. ~ is the process of linking ∆Em/AP to muscle contraction.
• Electrical events precedes mechanical events (2ms, 100ms)
• Twitch
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The Physiology of Muscles
Skeletal Muscles: ECC
Part III
Motor Unit
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Motor Units
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The Physiology of Muscles
Skeletal Muscles: ECC
Part III
3.6.2. Events at the neuromuscular junction:
3.6.2.1. Presynaptic end (α-motor neuron)
AP in presynaptic α-motor neuron terminals
Depolarization of plasma membrane of the presynaptic α-motor neuron axon terminals
[Δ 30mV]
Opening of Ca2+ channels at the active zones →↑Ca2+ permeability and
entry of Ca2+ into α-motor neuron axon terminals
Release of Ach from the synaptic vesicles into the synaptic cleft
(200-300 vesicles/exocytosis)
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3.6.2.2. Postsynaptic end
Diffusion of Ach to Postjunctional membrane → combination of Ach
with nAchR (107-108, 2α subunit) on the motor endplate
Conformational change → opening of the gate→↑ permeability of the
postjunctional membrane to Na+ and K+
Transient change in the Em→ depolarization → EPP
Depolarization of areas of muscle membrane adjacent to endplate and
initiation of AP
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Endplate Potential/EPP
i. A graded response (magnitude of depolarization α No of open Ach channels
ii. Transient (∵Ach is hydrolyzed to form choline and acetate).
iii. Amplitude: 50mV
iv. No voltage-gated Na+ and K+ channels at the endplate region
(∴ No AP, Na+, K+ channels are located on the muscle membrane
contiguous to the endplate)
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v. Ionic basis of EPP:
• Ach activated channel
• Independent of membrane potential
• Em is between EK+ and ENa+
vi. EPP depolarizes the contiguous membrane regions by electronic
conduction to threshold and AP is generated.
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3.6.3. Propagation of AP into the T-tubule & release of Ca2+ from the
terminal cisternae
A. Transverse Tubule (T-tubule)
i. It is an invagination of the surface of the sarcolemma
ii. It is found at the junction of A-I bands (at z-line in frog)
iii. One end of the tube is open to extracellular space, but its other
end is closed.
iv. Function: rapid transmission of AP from the cell membrane to
all the fibers on the muscle.
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B. Sarcoplasm Reticulum (SR)
i. It is an internal tubular structure that runs between the myofibrils.
ii. It is closed at both ends.
iii. It is not continuous with the sarcolemma.
iv. Functions:
• Stores Ca2+ in the terminal cisternae (lateral sacs)
• Uptake and release of Ca2+
NB
• Calsequestrin is sarcoplasmic protein that binds Ca2+
(1 calsequestrin = 43 Ca2+ )
• Triad: 2 lateral sacs + 1 transverse tubule
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3.6.4. The Activation of Muscle Proteins
3.6.4.1. Thick Filaments
a. Myosin (an actin binding protein)
b. 2 distinct structures:
• Myosin head (cross bridge):
actin-binding site
• ATP binding site (ATPase):
hydrolyzes ATP
3.6.4.2. Thin Filaments
a. Actins
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b. Troponins:
Small globular units located at intervals along tropomyosin molecules.
i. Troponin T: it binds other troponin components to tropomyosin
ii. Troponin I: inhibits the interaction of myosin with actin
iii. Troponin C: it has the binding site for Ca2+ that initiates contraction
Tropomysoin
i. A rod-shaped molecule stretched along each strand of thin filament.
ii.1 tropomyosin molecule covers seven actin monomers
iii. It blocks the binding sites of myosin on actin.
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Resting state
i. Interaction of thick and thin filaments is inhibited
ii. Troponin I & tropomyosin covers the sites where myosin heads bind to actin
Activated States:
Influx of Ca2+
↓
Binds to Troponin C (4 Ca2+)
↓
Conformational change in troponin
↓
Tropomyosin moves aside
↓
Exposes the myosin-binding sites on actin
↓
Myosin cross-bridge on the thick filament is exposed to actin filaments
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3.6.5. Generation of Tension
Cross-bridge cycle: 4 steps
1. Binding of the cross-bridge to actin
A+M* . ADP. Pi
A.M* + ADP + Pi
Actin binding
2. Bending of the cross-bridge producing movement of thin filament.
A. M*. ADP. Pi
A.M*.+ ADP + Pi
Cross-bridge movement
3. Detachment of the cross-bridge from the thin filament
A.M+ ATP
A+ M.ATP
Cross-bridge dissociation from actin
4. The cross-bridge returns to its original upright position to repeat the cycle.
M.ATP
M*. ADP. Pi
ATP hydrolysis
NB. Tension is generated by repetitive cross-bridge cycling.
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3.6.6. Relaxation of Muscle.
a. Removal of Ca2+ from the Myoplasm (<0.1µmol/l) into the SR.
b. For Ca2+ removal from the sarcoplasm the third ATP is consumed by
Ca2+-Mg2+ -ATPase
c. After removal of Ca2+ :
i. Troponin returns to its original conformational state.
ii. Tropomyosin inhibition of Myosin-Actin interaction is
restored.
iii. Cross-bridge cycling stops and the muscle is returned
to its resting state.
d. Breakdown of Ach by AchE.
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Regulatory function of ATP
i. Actin + Myosin +ATP + Ca2+
Contraction
ii. Actin+ Myosin + ATP – Ca2+
Relaxation
iii. In the absence of Ca2+ ATP is not hydrolyzed.
iv. 3 ATP molecules are needed:
a. For energizing the myosin cross-bridges
b. For dissociation of actinmyosin complex and initiation of relaxation
c. To pump out Ca2+ from the sacroplasm to sequester it into the SR
(Ca2+-Mg2+ - pump)
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Changes
a. Banding
•
•
•
•
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H-zone:
Z-line:
I-band:
A-band:
Disappears
Gets considerably darker
Narrower/smaller
κ
b. Contractile proteins:
NO CHANGE in length of myosin or actin
c. Sarcomere:
Shortens
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Ion channels involved:
i.
Voltage-gated Ca2+ channels (active zone, α-motor neuron)
ii.
Ligand-gated cationic channels (Ligand-gated Na+ channels, motor
endplate)
iii. Voltage-gated Na + channel (contiguous to the motor endplate).
iv. Voltage-gated Ca2+ channel (t-tubule)
v.
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RyR Ca2+-release channel (SR)
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Summary
Discharge of motor neuron
↓
Release of Ach at motor endplate
↓
Binding of Ach to nAchR
↓
↑gNa+ and gK + in endplate membrane
↓
Generation of EPP
↓
Generation of AP in muscle fibers
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Generation of AP in muscle fibers
↓
Inward spread of depolarization along T-tubules
↓
Release of Ca2+ from terminal cisterns of SR and diffusion to
thick and thin filaments
↓
Binding of Ca2+ to troponin C, uncovering myosin-binding
sites on actin
↓
Formation of cross-linkages between actin and myosin and
sliding of thin on thick filaments, producing movement
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Steps in relaxation
Ca2+ pumped back into SR
↓
Release of Ca2+ from troponin
↓
Cessation of interaction between actin and Myosin
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Rigor Mortis
a. It is a state of muscle contracture, ie., contraction produced without
AP and not followed by relaxation.
b. It is a contracture which occurs in the muscles after death. It starts in
small muscles (2-3hrs) after death and involves all muscles in 12 hrs.
c. The rigidity is due to depletion of ATP from the muscle. Calcium
diffuses out of the SR & can not be recollected by the Calcium pump.
d. Calcium initiates muscle contraction using the remaining ATP
molecules, relaxation does not occur because calcium is not
recollected back into the SR, and no ATP is available to disconnect
the myosin heads from actin.
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e. It disappears when muscle fibers are autolysed by lysosomal enzymes
released after death.
f. It starts to disappear 14hrs after death and completed in 24hrs. High
environmental temperature accelerates the appearance and disappearance of
rigor mortis.
g. The extent of rigor mortis is used medically to determine the time of death.
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4.2. Cardiac Muscle Vs Skeletal Muscle
4.2.1. Cardiac Muscle.
1. A cardiac myocyte has a single nucleus which is smaller (ɵ = 15-20
µm, L = 100µm)
2. Has abundant amount of mitochondria (30%) + myoglobin which
makes it fatigue resistant (myoglobin facilitates the transport of
oxygen from the sarcolemma to the mitochondria)
3. A cardiac cells are joined end-to-end by intercalated discs:
i. Attach one cell to the next by means of desmosomes
ii. Connect the thin filament of the myofibrils of adjacent cells.
(Mechanical + electrical coupling)
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iii. Contain gap junctions which is synchronizing the contractions of
heart muscle cells.
4. The T-tubule is larger and it is found at z-line
5. The SR - makes contact with T-tubule and the cell membrane.
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4.3. Excitation-Contraction Coupling/Electrochemical Coupling
(Cardiac Vs Skeletal)
4.3.1. Cardiac Muscle.
1. Ca2+- release from the SR is triggered by Ca2+ (not by membrane
Depolarizations). (Extracellular Ca2+ →SR (is responsible for
prolonged plateau phase).
2. T-Tubule (DHPR) contains Ca2+ channel (through which Ca2+ enters
the cell during the AP).
3. SR-RyR containing Ca2+- release channel is opened by influx of Ca2+
from the T-Tubule.
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4. Amount of Ca2+- release from the SR in under physiologic control.
a. Hormones (catecholamines) → ↑ the amount of Ca2+ entering
the cell → ↑IC Ca2+
b. Pump (Na+-Ca2+ Exchanger, ↑1Ca2+, ↓3Na+) is increasing the
Ca2+ in the cell.
Clinical correlates
• Familial cardiomyopathic hypertrophy
• Hypertrophy
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5.0. SMOOTH MUSCLE
5.1. Introduction
a. It is important in regulation of the airways, blood vessels, GIT, and
hollow organs (bladder, uterus...)
b. It is controlled by intrinsic factors (inherent rhythmicity): ANS +
HORMONES.
c. It produces slower and longer-lasting contractions (slow and
sustained) (↓rates of cross-bridge cycling → LATCH STATE →
maintain TONE and little energy consumed)
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5.2. Smooth Muscle Vs Striated Muscle.
5.2.1. Smooth Muscle.
1. It has NO STRIATIONS (sparse thick filaments and absence of
transverse registration).
2. Has elongated spindle shaped cells with a single nucleus
(L = variable size, attached in series to bear equal stress).
3. Sarcomeres are absent.
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4. The myofilaments are :
a. Thick filaments: myosin
b. Thin filaments: actin and tropomyosin (No troponin)
c. Thick and thin filaments are dispersed through out the cell.
They are not arranged in strictly ordered pattern.
d. Thin filaments are attached to dense bodies
(functional equivalents of Z)
i. DENSE BODIES: are found in cell membrane and cytoplasm
composed of -actinin.
5. Tubules: T-tubules are absent and the SR is rudimentary
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5.3. Excitation - Contraction Coupling (Smooth M.Vs Striated M.)
• Cross-bridge cycling is regulated by Ca2+- induced phosphorylation of
myosin.
1. Myosin cross-bridge has 4 light chain
2. Myosin can not bind to actin unless one of these light chains
(LC20) is phosphorylated.
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a. Phosphorylation of LC20 is by Myosin Light Chain Kinase (activated
by Calmodulin, 4Ca2+, Kinase - calmodulin - Ca2+- complex)
b. Ca2+ can enter the cell in a variety of ways:
i. Stimulation by a neurotransmitter (receptor-activated Ca2+ channel)
ii. Voltage-operated Ca2+channels
iii. Release from SR
(SR-IP3R) (IP3R = inositol triphosphate receptors)
3. The light chains are dephosphorylated by the enzyme Myosin Light
Chain Phosphorylase.
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Summary ECC smooth muscle
Binding of Ach to mAchR
↓
Increased Ca2+ influx into the cell
↓
Activation of calmodulin-dependent myosin light chain kinase
↓
Phosphorylation of myosin
↓
Increased myosin ATPase activity and binding of myosin to actin
↓
Contraction
↓
Dephosphorylation of myosin by myosin light chain phosphatase
↓
Relaxation, or sustained contraction due to the latch bridge and other
mechanisms
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